Antimicrobial activity of gemfibrozil and related compounds...

Details Antimicrobial activity of gemfibrozil and related compounds... Antimicrobial activity of gemfibrozil and related compounds...

1999-11-10

2003-03-11

Russel, Jeffrey E. (Department: 1653)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving oxidoreductase

C435S189000

Reexamination Certificate

active

06531291

ABSTRACT:

BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced by a number in brackets. Full citations for these publications may be found listed by number at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Gemfibrozil (GFZ) is a compound that has been utilized as a drug for increasing intracellular accumulation of hydrophilic anionic agents (U.S. Pat. No. 5,422,372, issued Jun. 6, 1995) and as a lipid regulating composition (U.S. Pat. No. 4,859,703, issued Aug. 22, 1989). Gemfibrozil has been shown to be effective in increasing the amount of cholesterol excreted in to bile. (Ottmar Leiss et al., Metabolism, 34(1):74-82 (1985)). Gemfibrozil is described in U.S. Pat. No. 3,674,836 and in The Merck Index, 11 ed., Merck & Co., Inc. Rahway, N.J. 1989; #4280. Gemfibrozil, a drug which therapeutically lowers triglycerides and raises HDL-cholesterol levels, previously has not been reported to have antimicrobial activity. (Brown, 1987; Oliver et al., 1978 and Palmer et al., 1978).
SUMMARY OF THE INVENTION
The present invention provides for a method of inhibiting activity of an enoyl reductase enzyme in a cell which comprises contacting the cell with a compound having the structure:
wherein each of R
1
, R
2
, R
3
, R
4
, R
5
and R
6
is independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —OH, —OR
7
, —CN, —COR
7
, —SR
7
, —N(R
7
)
2
, —NR; —COR
8
, —NO
2
, —(CH
2
)
p
—OR
7
, —COSR
7
, —COOH, —CONH
2
, —NH
2
, a straight chain or branched, substituted or unsubstituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, C
3
-C
10
cycloalkenyl, thioalkyl, methylene thioalkyl, acyl, phenyl, substituted phenyl, or heteroaryl;
wherein L is alternatively —N—, —S—, —C— or —C—;
wherein R
7
is independently selected from the group consisting of —H, —F, —Cl, —Br, —I, —OH, —CN, —COH, —SH
2
, —NH
2
, —NHCOH, —(CH
2
)
p
OH, a straight chain or branched, substituted or unsubstituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, C
3
-C
10
cycloalkenyl, thioalkyl, methylene thioalkyl, acyl, phenyl, substituted phenyl, or heteroaryl;
wherein A is selected from the group consisting of —N
2
—, —NH—, —C═C═CH
2
—, —C≡C—C
2
HOH—, —C≡C—CH
2
—, —CH
2
—CH
2
—O—, —CH
2
—CH
2
—CH
2
—O—, —S—, —S (═O)
2
—, —C═O—, —C═O—O—, —NH—C═O—, —C═O—NH—;
wherein Q is independently an integer from 1 to 10, or if Q is 1, A may be a (C
1
-C
10
)-alkyl chain, (C
1
-C
10
)-alkenyl chain or (C
1
-C
10
)-alkynyl chain which is branched or unbranched, substituted or unsubstituted and is optionally interrupted 1 to 3 times by —O— or —S— or —N—;
wherein X is —CO
2
—, —CH═CH
3
, phenyl, substituted phenyl, or heteroaryl, —O-phenyl(CH
3
)
2
, —C(CH
2
)
2
—CO—NH
2
, —C(CH
2
)
2
—COOH;
or a pharmaceutically acceptable salt or ester thereof, which compound is present in a concentration effective to inhibit activity of the enzyme.


REFERENCES:
patent: 4859703 (1989-08-01), Krause
patent: 4891220 (1990-01-01), Donzis
patent: 5422372 (1995-06-01), Silverstein et al.
patent: 5837480 (1998-11-01), Sacchettini et al.
patent: 97/31530 (1997-09-01), None
patent: 99/37800 (1999-07-01), None
Bergler et al. The enoyl-[acyl carrier protein] reductase . . . Eur. J. Biochem. vol. 242, pp. 689-694, 1996.*
Cardon et al. Kinetic and Structural Investigation of Acyl . . . J. Biol. Chem. vol. 258, No. 8, pp. 4802-4807, Apr. 25, 1983.*
Clements et al. Irreversible inhibition of fatty acid synthase . . . Biochem. J. vol. 207, pp. 291-296, 1982.*
Heath et al. Regulation of Fatty Acid Elongation and Initiation . . . J. Biol. Chem. vol. 271, No. 4, pp. 1833-1836, Jan. 26, 1996.*
Vernon et al. The Presence of Essential Arginine Residues . . . Biochim. et Biophys. Acta. vol. 788, pp. 124-131, 1989.*
The Merck Index, 10th ed., Merck & Co., Inc., Rathway, N.J., 1983, #4246.

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